Abstract

Background There are scarce data available on transcatheter mitral valve replacement (TMVR), and these have been limited to procedural results, with no follow-up status reported.

Objectives The goal of this study was to evaluate the feasibility, procedural results, and 6-month follow-up outcomes after TMVR with a mitral transcatheter heart valve (Fortis, Edwards Lifesciences, Irvine, California).

Methods We report a series of 3 patients (mean age 71 ± 9 years, 2 men) who had TMVR under a compassionate clinical use program. All patients treated had functional mitral regurgitation (MR) secondary to ischemic cardiomyopathy (prior bypass surgery in all cases; left ventricular ejection fraction between 25% and 30%) and were considered to be at very high surgical risk (mean Society of Thoracic Surgeons score: 9.3).

Results The procedure was performed through the transapical approach, and the valve was successfully implanted in all cases, with no major complications. At hospital discharge, echocardiographic evaluation revealed trace residual MR in 2 patients and no MR in 1 patient. The mean transvalvular mitral gradient was ≤4 mm Hg in all patients. At the 3-month follow-up, the valve function remained unchanged, and transesophageal echocardiography and computed tomography showed no structural failures. All patients had improvements in functional status, in exercise capacity as evaluated by 6-min walk test, and in quality of life. At 6-month follow-up, all patients remain alive, without hospital readmission for heart failure and with New York Heart Association functional class ≤II.

Conclusions TMVR with this valve is feasible and is associated with good outcomes. Optimal valve functional results were obtained acutely and were sustained at 6-month follow-up in all patients. Further studies with a larger number of patients and longer follow-up are warranted.

Severe mitral regurgitation (MR) represents the second most prevalent valvular heart disease in western countries (1). Although there is a consensus on the advisability of surgery in patients with symptomatic severe MR (3+/4), up to one-third to one-half of patients requiring mitral valve repair/replacement are deemed to be at too high risk for surgery (2,3). When the operative risk is unacceptable, percutaneous edge-to-edge mitral repair (MitraClip System, Abbott Vascular, Santa Clara, California) has emerged as a valid alternative to surgery with low procedural risk (4,5). However, specific anatomical conditions are required to obtain satisfactory results, with increasing rates of procedural failure and poorer clinical outcomes when these criteria are not taken into account (6–8). Therefore, a significant proportion of noncandidates for surgery for whom percutaneous mitral repair is not an appropriate option remain.

Transcatheter mitral valve replacement (TMVR) has recently emerged as a new therapeutic option for the treatment of mitral valve disease. However, current experience is limited to procedural results in very few cases worldwide (9–12), and follow-up status has not been reported. The objective of this study was to evaluate the feasibility, procedural results, and 6-month follow-up outcomes after TMVR with the mitral transcatheter heart valve (Fortis, Edwards Lifesciences, Irvine, California).

After multidisciplinary team evaluation, all patients were considered to be at prohibitive risk for standard surgical valve repair/replacement. All patients were evaluated and treated under a Special Access Program approved by Health Canada. This is a clinically oriented program that evaluates, on a case-by-case basis, requests for access to nonmarketed drugs or devices for treatment, diagnosis, or prevention of serious or life-threatening conditions when conventional therapies have been considered and ruled out, have failed, are unsuitable, and/or unavailable. After Health Canada approval, all patients provided signed informed consent for the procedures and for retrospective data collection and reporting.

Fortis mitral transcatheter heart valve

The valve (Figure 1) comprises a self-expanding, nitinol frame, trileaflet Resilia bovine pericardial tissue, an atrial flange, and 2 opposing paddles that capture the native mitral leaflets and secure them to the frame, forming the primary attachment mechanism. The 29-mm prosthesis (the only available size to date) is crimped and loaded into a 42-F transapical delivery system. The 29-mm valve is suitable in patients with native annular diameter distance at the A2-P2 level between 30 and 44 mm.

(A) The Fortis mitral transcatheter heart valve has 3 different parts: the atrial flange, the ventricular side (or valve body), and 2 paddles (black arrows). The paddles are opened once the prosthesis enters into the left ventricular cavity and are oriented using echocardiography guidance to capture the native mitral leaflets. (B) Fluoroscopic images of the Fortis valve after full deployment. AS = atrial side; VS = ventricular side.

Procedural steps

The procedures were performed under general anesthesia with hemodynamic monitoring in an operating room with fluoroscopic and echocardiographic imaging capabilities. Epidural anesthesia was used in all patients to improve control of post-procedural chest pain and to facilitate post-intervention recovery. The approach consisted of direct puncture close to the ventricular apex through a small left lateral thoracotomy, and then the delivery system was advanced directly through the ventricular incision. Transesophageal echocardiography (TEE) guided the ventricular puncture point to obtain delivery system coaxiality with the mitral annulus (Figure 2A). The mitral valve was crossed with a Fogarty catheter (Edwards Lifesciences) to ensure that the guide wire was free from chordal entanglement (Figure 2B). To decrease the risk of wire-induced perforation, a soft J-tip guide wire was positioned into the right superior pulmonary vein and was subsequently exchanged for a stiff J-tip guide wire with a soft tip using a multipurpose catheter. The delivery system with the crimped valve was advanced antegradely over the stiff wire up to the midventricular cavity. At this point, the paddles were partially exposed, and TEE guidance was used to evaluate their orientation (Figure 2C). After confirming that the paddles were oriented between the papillary muscles, the paddles were fully exposed and opened in preparation for leaflet capture. The delivery system was advanced to capture the mitral leaflets at the A2-P2 level (Figure 2D). After leaflet capture was confirmed, the atrial flange was released (Figure 2E). The valve was then released by unsheathing the ventricular portion (Figure 2F). Rapid pacing is not required for the delivery of the valve. We elected to use brief, rapid pacing for catheter retrieval and apical repair to prevent potential myocardial tears. Anticoagulation during the procedure was obtained with intravenous heparin, and the dose was adjusted to obtain an activated clotting time >250 s. Aspirin (80 mg) was administered before and after the implant procedure, and warfarin was started after the procedure and continued for at least 3 months. In patients with baseline atrial fibrillation, warfarin was to be continued indefinitely and aspirin was continued for at least 3 months.

Transesophageal echocardiogram images obtained during transcatheter mitral valve replacement with the valve. (A) Midesophageal intercommissural view. Finger exploration of the ventricular apex is used to locate the appropriate access point (red arrow), which allows for appropriate coaxiality of the system with the mitral annulus while avoiding the subvalvular apparatus (red dotted line). (B) Midesophageal intercommissural view. Maneuver with the Fogarty catheter to ensure that the catheter is not tangled within the mitral chordae. (C) Transgastric short-axis view at the mitral leaflet and subvalvular level. The system is located at the midventricular cavity. Paddles are opened (blue and red asterisks). This view is used to verify the perpendicularity of the paddles with respect to the mitral annulus at the A2-P2 level. (D) Midesophageal long-axis LVOT view. Once the position of the paddles is verified, the system is advanced to capture the mitral leaflets. (E) Midesophageal long-axis LVOT view showing the atrial frame released. The ventricular frame is still unreleased. (F) Midesophageal long-axis LVOT view. The ventricular frame of the valve has been released. The nose cone is still in the LV cavity. AL = mitral anterior leaflet; Ao = aorta; LA = left atrium; LV = left ventricle; LVOT = left ventricular outflow tract; PL = mitral posterior leaflet; RV = right ventricle.

Procedural success was defined as the implantation of a functioning valve within the mitral annulus, without intraprocedural mortality or significant (moderate or severe) residual MR and/or mitral stenosis.

All in-hospital, 30-day, and follow-up events were recorded and collected in a dedicated database. Adverse events were defined according to the Valve Academic Research Consortium-2 criteria (13). There was no systematic evaluation of the patients by a neurologist. Before hospital discharge, an echocardiographic (transthoracic and transesophageal) evaluation of the valve prosthesis was performed.

All patients had a clinical visit and transthoracic echocardiography (TTE) examination at the 1- to 3-month and 6-month follow-ups. A TEE and 3-dimensional (3D)–CT examinations were also performed at the 3-month follow-up. The presence and severity of MR were evaluated according to guidelines (14). The 3D-CT was performed to determine the integrity of the valve prosthesis (i.e., inspect for frame fractures) and the anatomic relation of the valve to the left ventricle and the left atrium.

The functional status, exercise capacity, and quality of life of the patients were evaluated at baseline (during the week before the procedure) and at the 3- and 6-month follow-ups. Functional status was evaluated using the NYHA functional class and the Duke Activity Status Index (DASI) questionnaire. The DASI questionnaire consists of a 12-item scale ranging from 0 (worst) to 58.2 (best) that evaluates the ability to perform common activities of daily living. Exercise capacity was evaluated with the 6-min walk test (6MWT), which was conducted according to a standardized protocol, using a 30-m internal flat corridor with 2 orange traffic cones (15). Patient quality of life was evaluated with the Kansas Cardiomyopathy Questionnaire (16).

Results

A series of 3 patients were successfully treated with the mitral transcatheter heart valve.

Table 1 summarizes the main baseline characteristics of the patients. All patients had a previous history of coronary artery disease with prior coronary artery bypass graft and symptomatic ischemic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤30% in all patients). All had at least 1 admission for heart failure within the 6 months prior to the procedure. Patients were rejected for conventional mitral surgery due to left ventricular dysfunction, previous cardiac surgery, and moderate renal dysfunction. All patients had an MR ≥3+ of functional origin. In 2 patients, the MR was a consequence of a posterior leaflet retraction in the context of previous inferior myocardial infarction. In another patient, the mechanism was mainly tenting and annular dilation.

Procedural details are provided in Table 2. The procedure was successful and without major complications in all cases. The valve was correctly implanted in all patients, and per-procedural TEE revealed a minor (1+) residual leak in 2 patients and no residual leak in 1 patient. The transmitral gradient was ≤4 mm Hg in all cases, with a mean of 3 mm Hg. The procedural time, defined as from delivery system insertion to valve deployment, ranged from 25 to 44 min. Post-procedural complications consisted of an acute worsening of renal function (without requiring hemodialysis) in 1 patient, and per-procedural bleeding requiring blood transfusion in another patient. There were no other in-hospital complications, and all patients were discharged between 7 and 13 days post-intervention.

Echocardiographic examinations (TTE and TEE) before hospital discharge revealed the absence of MR in 1 patient and trivial MR in 2 patients (Figure 3). None of the patients presented an increase of the aortic outflow gradient after valve implantation.

Echocardiograms of the 3 patients following transcatheter mitral valve replacement. No significant mitral leaks were found by echocardiography post-valve implantation.

Follow-up outcomes

There was no mortality at 6-month follow-up. Patient 2 was hospitalized 30 days after the procedure because of gastrointestinal bleeding in the context of supratherapeutic international normalized ratio levels (international normalized ratio: 11.7). Endoscopy revealed esophageal varices and signs of recent bleeding; warfarin and aspirin were discontinued, and clopidogrel was started. There were no other complications.

At the 3-month follow-up, all patients showed an improvement in NYHA functional class, DASI functional status, distance walked in the 6MWT, and quality of life (Table 3 and Central Illustration). TTE and TEE revealed normal prosthesis function in all patients, with a trace leak in 1 patient and no MR in another patient. Transmitral gradients remained similar to those observed in the immediate post-procedural period (between 2 and 3 mm Hg). No thrombus was observed. The mean gradients in the left ventricular outflow tract (LVOT) were between 2 and 5 mm Hg, and LVEF was similar to baseline. Functional status improvement persisted at 6 months, with all patients in NYHA functional class ≤II.

CT scan images of the 3 patients at the 3-month follow-up are shown in Figure 4. No fractures of the valve frame were detected, nor was any erosion of the posterior aortic wall (Figure 4). Adequate space at the level of the outflow tract was evident in all cases (Central Illustration).

(A) Long-axis view of patient 1 showing an optimal LVOT clearance (red arrows), and no erosion in the aortic sinus side (asterisk). (B) Short-axis view of patient 2 at the mitral annulus level. (C) Sagittal view of patient 3 showing the apical scar (black arrow) at the puncture level, and the interaction between the flexible FORTIS struts and the aorta at the aortic sinus level (asterisk). RCA = right coronary artery; other abbreviations as in Figure 2.

Discussion

This initial experience of TMVR with the Fortis valve demonstrates the feasibility and safety of the procedure. Furthermore, optimal valve performance was achieved in all cases, with no significant residual leaks or transvalvular gradients, and valvular function was maintained at the 3-month follow-up. No structural failures of the device, as evaluated by echocardiography and CT, were detected at 3 months. This translated into a significant improvement in functional status and quality of life for all patients at the 3- and 6-month follow-ups.

There are several reports of TMVR using balloon-expandable aortic valve systems in the mitral position in patients with severe calcified mitral disease (mitral stenosis and/or mitral regurgitation) who were deemed to be at high surgical risk (17–22). Similar to aortic valve implantation, the presence of severe annular mitral calcification seems to be pivotal for ensuring valve prosthesis anchoring and stability, and this precludes the use of these valve platforms in the setting of nonsevere calcified mitral disease. More recently, the procedural results of the 10 first-in-man cases using a dedicated transcatheter mitral valve platform in patients with isolated MR have been reported, including 5, 3, and 2 cases with the Fortis, CardiaAQ (CardiAQ Valve Technologies, Irvine, California), and Tiara (Neovasc, Richmond, British Columbia, Canada) devices, respectively (9,10,12). In addition, 2 patients had implantation of the Tendyne valve (Tendyne Holdings Inc., Roseville, Minnesota) (11), but the system was removed within 2 h after successful implantation, and the patients finally underwent standard surgical mitral surgery. The high periprocedural mortality rates for these first 10 patients represent an early experience in relatively highly comorbid patients with no or few other therapeutic options, treated mainly under compassionate use. The main causes of mortality included technical issues leading to valve prosthesis dislocation (n = 1), post-operative complications leading to multiorgan failure (n = 4), and suspected valve thrombosis within 30 days after the procedure (n = 1). Appropriate anatomical screening by echocardiography and CT, as well as access point planning, seems to be key for procedural success. In our experience, apart from CT-based pre-planning of the optimal puncture site, careful manual evaluation guided by TEE with the ventricular apex exposed was very important for the final selection of the puncture site to achieve optimal coaxiality of the delivery system with the native mitral valve (Figure 2A).

Apart from technical difficulties, the mixed results obtained in the overall initial TMVR experience highlight the importance of patient selection as well as the potential challenges of a thoracotomy and apical approach. Besides the importance of noncardiac comorbidities, the presence of an LVEF <20% may be associated with further reduction of the LVEF after the procedure (23,24), leading to persistent heart failure and death. In addition, the myocardial injury associated with the transapical approach may further contribute to decreased LVEF (25). All patients included in our small series had an LVEF of 25% to 30%, and none of them experienced decompensated heart failure after the procedure. Also, potential challenges with transapical procedures are relatively well understood. In addition to potential myocardial tears during transapical access hemostasis, pain associated with left thoracotomy has been shown to have a major negative effect on patients undergoing transapical aortic valve procedures (26). We have previously shown the usefulness of adequate pain control with the use of epidural analgesia in transapical aortic valve implantation (26), and this approach was also applied to our TMVR procedures, and may have contributed to the successful results obtained in our initial TMVR experience.

There is no evidence concerning the most appropriate antithrombotic treatment after TMVR. After surgical mitral valve replacement with a bioprosthesis, all guidelines recommend selected or systematic anticoagulation therapy in addition to aspirin for 3 months, and then aspirin indefinitely (27). This was the regime applied in our patients (2 were already on warfarin therapy due to atrial fibrillation and were intended to remain on warfarin indefinitely), although 1 of them presented with gastrointestinal bleeding in the weeks after the procedure and required cessation of anticoagulation therapy. This patient was treated with clopidogrel, and no thromboembolic events had occurred at the 6-month follow-up. However, in May 2015, Edwards Lifesciences temporarily halted the prospective Fortis clinical trial due to valve thrombus noted in some of the valves. This suggests that a strict anticoagulation regime may be needed after TMVR. Future studies are needed to determine the best type and duration of antithrombotic treatment after these procedures.

This is the very first report with systematic 6-month follow-up data after TMVR. This early follow-up showed that valve function was maintained, with no structural failures. The systematic improvement in patients’ functional status and quality of life, with no rehospitalizations due to decompensated heart failure, are encouraging. However, a close, longer-term follow-up is needed to confirm these promising early results.

Study limitations

The main limitations of this study are the small number of patients and the lack of long-term follow-up. After this initial experience, a larger number of patients and a longer follow-up will be needed to determine the final safety and efficacy results associated with this technology.

Conclusions

In this initial experience including 3 patients, TMVR with the Fortis mitral transcatheter heart valve was feasible and was associated with good outcomes at the 6-month follow-up, with a low complication rate and sustained valve performance. Continued advancements in anatomical evaluation, technical ease, pre-procedural planning, and post-procedural management will play an important role in the success of TMVR procedures. Further studies are warranted.

Perspectives

COMPETENCIES IN MEDICAL KNOWLEDGE: TMVR can be performed with a low midterm complication rate in patients with isolated, severe MR who are at very high or prohibitive risk of complications with open mitral valve surgery.

TRANSLATIONAL OUTLOOK: Additional studies involving a larger number of patients and longer follow-up are necessary to better define the clinical and anatomical characteristics of the patients most able to benefit from this therapeutic approach.

Footnotes

Drs. Abdul-Jawad Altisent and del Trigo are supported by a research PhD grant from the Alfonso Martin Escudero Foundation. Dr. Rodés-Cabau has received research grants from Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. William O’Neill, MD, served as Guest Editor for this paper.

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